Dual-specificity tyrosine phosphorylation-regulated kinase (DYRK) is a serine/threonine kinase, is very highly conserved in evolution, and plays a variety of roles in the central nervous system development and function. Humans have five types of isoforms, such as DYRK1A, DYRK1B, DYRK2, DYRK3, and DYRK4, among these, DYRK1A has been widely studied and has received the most interest related to Down syndrome and degenerative brain diseases. A DYRK1A gene is localized in the Down Syndrome Critical Region (DSCR) of human chromosome 21. As the DYRK1A gene turns out to be a decisive factor in cognitive impairment which typically appears in patients with Down syndrome, the DYRK1A gene has received more interest. Patients with Down syndrome suffer from cognitive impairment and memory impairment, which mainly appear in Alzheimer's disease from around 35-40 years of age. Interestingly, the expression and activity increase of DYRK1A is shown in patients with degenerative brain diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and Pick's disease, as well as Down syndrome.
Alzheimer's disease is largely accompanied by the two types of neuropathology: an amyloid plaque which is a cell accumulation of the insoluble precipitate of amyloid β peptide; and the formation of the intracellular neurofibrillary tangles consisting of an aggregate of the hyperphosphorylated tau. It is known that DYRK1A directly phosphorylates key proteins in the formation of these neuropathologies, such as Tau, amyloid β precursor protein (APP), and Presenilin 1 (PS1), and thus DYRK1A is associated with Alzheimer's disease. In addition, DYRK1A plays an important role in other degenerative brain diseases, and it is confirmed that DYRK1A affects the formation of Lewy body which is the core neuropathology of Parkinson's disease, through the phosphorylation of α-synuclein, and affects the onset of Huntington's disease through the phosphorylation of HIP-1. These facts show that DYRK1A contributes to the formation of various neuropathologies through the phosphorylation of Tau, APP, PS1, α-synuclein, HIP-1, etc. and results in the cognitive and memory impairment in a variety of degenerative brain diseases, as well as Down syndrome.
In fact, a transgenic mouse model which overexpresses DYRK1A of human or mouse shows the phenotype of Down syndrome, including deficiency and developmental delays of spatial learning and motor neuron that depend on the hippocampus, which implies an important function of DYRK1A in the mental retardation associated with Down syndrome.
The existing FDA-approved drugs as a therapeutic agent for Alzheimer's disease mainly act in a manner to improve the abnormality of the neurotransmitter and have a limited effect to alleviate some of the symptoms of the disease. Future drug development strategy requires a more fundamental treatment approach in such a manner to inhibit the amyloid plaque, the neurofibrillary tangles, etc. directly associated with the onset of Alzheimer's disease. However, it is a widely-accepted theory that it is also difficult to expect that this existing fundamental approach has an adequate therapeutic effect with only improvement for a single neuropathology, thereby there is a need for the new strategy of the multi-target method which can control the amyloid plaque and the neurofibrillary tangles at the same time.
In view of this, the present inventors have tried to develop a drug to target DYRK1A during the study of the strategy to control the amyloid plaque and the neurofibrillary tangles at the same time, have confirmed that the pyridine-based compound according to the present invention is structurally different from the existing known DYRK1A inhibitory substance, the inhibitory effect is more excellent, and the selectivity for DYRK1A is excellent, and have completed the present invention.
In addition, according to a recent study, DYRK1A also receives an interest as a target in developing therapeutic agents for type 1 diabetes other than Down syndrome and degenerative brain diseases. It was confirmed by several research groups that DYRK1A is involved in the proliferation control of the beta cells, which are the insulin-producing cells of the pancreas, through NFAT signaling, and when DYRK1A is inhibited, the proliferation of these cells is activated. After all, an effective inhibitory drug of DYRK1A promotes insulin production and secretion by activating the proliferation of pancreatic beta cells, and thus a therapeutic effect in patients with type 1 diabetes can be expected.
In addition, DYRK1A is highly expressed in a few cancer species, the typical examples of which are brain tumors and hematologic cancers. DYRK1A is reported to be involved in the generation and progression of cancer through the phosphorylation of intracellular various factors (p27, cyclin Dl, DREAM, C-myc, Sprouty, etc.). In particular, Sprouty is an important factor in regulating the recycling of EGFR which is important for the maintenance of the stemness of cancer stem cells, and the anticancer effect can be expected in a manner to inhibit the stemness of the cancer stem cells by inhibiting DYRK1A.
The compound derived from the present invention shows a relatively high inhibitory effect on DYRK1A, but the inhibitory effect is also confirmed on DYRK1B, DYRK3, and DYRK4, and thus the anticancer effect can be expected through the control of the cell cycle in which these isoforms are known to be mainly involved.